Metabolism of trichloroethene--in vivo and in vitro evidence for activation by glutathione conjugation.
The metabolism of trichloroethene by glutathione conjugation was investigated in rat liver subcellular fractions and in male rats in vivo. In the presence of glutathione, rat liver microsomes transformed [14C]trichloroethene to S-(1,2-dichlorovinyl)glutathione (DCVG) identified by gas chromatography mass spectrometry after hydrolysis to the corresponding cysteine S-conjugate and chemical derivatisation. In bile of rats given 2.2 g/kg trichloroethene. DCVG was present in concentrations of 5 nmol (7 ml bile collected over 9 h) and identified by thermospray mass spectrometry after HPLC-purification. E- and Z-N-acetyl-dichlorovinyl-L-cysteine (3.1 nmol present in the pooled 24-h urine) were identified by GC/MS after methylation and butylation as urinary metabolites of trichloroethene (2.2 g/kg, orally). The presented results demonstrate that glutathione-dependent metabolism of trichloroethene is a minor route in the biotransformation of this haloalkene in rats. Formation of S-(1,2-dichlorovinyl)-glutathione, processing to S-(1,2-dichlorovinyl)-L-cysteine and metabolism of this S-conjugate by cysteine beta-lyase in the kidney to reactive and genotoxic intermediates may account for the nephrocarcinogenicity observed after long time administration of trichloroethene in male rats.
Dekant
W
W
Institut für Toxikologie, Universität Würzburg, F.R.G.
Koob
M
M
Henschler
D
D
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics*
D006710:Homocysteine; C051126:S-(1,2-dichlorovinyl)homocysteine; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; D014241:Trichloroethylene; D005978:Glutathione; D000111:Acetylcysteine